1-Substituted diazen-1-ium-1,2-diolates, a class of nitric oxide (NO) donor compounds that spontaneously release NO at different rates, were used to investigate the effect of NO release rate upon the oxidation of low density lipoprotein (LDL). All donor compounds conferred an inhibitory effect upon the oxidation of LDL; however, the effect exhibited a biphasic dependence upon the rate of NO release. The NO release rate that maximally inhibited oxidation was dependent upon the rate of oxidation. When LDL was rapidly oxidized by copper(II) sulfate, a faster release rate was more effective. In contrast, when LDL was oxidized slowly by 2,2'-azobis-2-amidinopropane hydrochloride, a slower release rate was most effective. This biphasic relationship between NO release rate and the duration of inhibition was also demonstrated when LDL oxidation was initiated with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium, a peroxynitrite generator. We conclude that the antioxidant ability of NO is dependent not only upon the rate of its release from NO donors, but also upon the rate of oxidation. This conclusion is supported by a kinetic model of LDL oxidation in the presence of NO. [unreadable]